Table 1.
Clinical trials of metabolic modulating agents in Major Depressive Disorder (MDD).
| Reference | Participants (N, % Female) | Age (SD) * | Medication | Comparator | Diagnosis | Enrichment | Outcome Measure and Duration | Result |
|---|---|---|---|---|---|---|---|---|
| Statin | ||||||||
| Ghanizadeh et al. 2013 | N = 68, 63.2% | 32.5 (10.2) and 31.7 (9.3) | fluoxetine (40 mg) + lovastatin (30 mg) | Fluoxetine (40 mg) + placebo | DSM-IV MDD | none | HDRS, 6 week RCT | Reduction of 12.8 (6.3) vs. 8.2 (4.0) p < 0.001 favouring lovastatin |
| Haghighi et al. 2014 | N = 60, 56.6% | 33.1 (8.9) and 31.4 (7.8) | citalopram (40 mg) + atorvastatin (20 mg) | citalopram (40 mg) + placebo | DSM-5 MDD | none | HDRS, 12 week RCT | week 12 HDRS atorvastatin: 19.63 (3.16) placebo: 22.03 (3.58) |
| Gougol et al. 2015 | N= 48, 60.4% | 36.4 (8.1) and 34.2 (10.8) | fluoxetine (40 mg) + simvastatin (20 mg) | fluoxetine (40 mg/day) + placebo | DSM-IV MDD | none | HDRS, 6 week RCT | group × time interaction favouring simvastatin (F (1.88, 78.94) = 3.78, p = 0.02) (Cohen’s d at week 6: 0.61) |
| Abbasi et al. 2015 | N = 46, 32.6% | 56.9 (6.9) and 57.7 (7.3) | simvastatin (20 mg/day) | atorvastatin (20 mg/day) | DSM-IV MDD | CABG in the last 6 months | HDRS, 6 week RCT | significant effect for time × treatment interaction favouring simvastatin s (F (1.62, 71.06) = 3.41, p = 0.048) |
| Kim et al. 2015 | N = 300, 39.6% | 60.3 (10.8), 58.9 (12.9), 60.4 (10.8), 59.3 (10.0) | escitalopram + statins | Escitalopram only, statin only, placebo only | DSM-IV MDD | acute coronary syndrome (ACS) | HDRS, 24-week RCT with 1-year follow-up | statin use associated with higher 1 year response rate 2.23 (1.11–4.51) p = 0.025 |
| Berk et al. 2020 | N = 130, 60%, | 20.2 (2.6) | Rosuvastatin (10 mg) | Aspirin (100 mg) or placebo | DSM-IV MDD | None | MADRS, 12-week RCT | no difference between rosuvastatin and placebo (−4.2, 95%CI (−9.1, 0.6), p = 0.089) |
| Giorgi et al. 2021 | Meta-analysis | statins compared to placebo in 5 RCT at 8 weeks (N = 255, SMD = −0.48, 95%CI = −0.74 to −0.22) and 12 weeks (N = 134, SMD = −0.47, 95%CI = −0.89 to −0.05) | ||||||
| Poly Unsaturated Fatty Acid (PUFA) | ||||||||
| Liao et al. 2019 | Meta-analysis | Beneficial effect of omega-3 polyunsaturated fatty acids on depression symptoms in 26 RCTs (SMD = −0.28, p = 0.004) | ||||||
| Luo et al. 2020 | Meta-analysis | n-3 PUFAs were superior to placebo in 10 RCTs (SMD: 1.243 ± 0.596; 95%CI: 0.060~2.414) both the high (SMD: 0.908 ± 0.331; 95%CI: 0.262, 1.581) and the low-dose (SMD: 0.601 ± 0.286; 95%CI: 0.034, 1.18) n-3 PUFAs were superior to placebo, and the efficacy of high-dose n-3 PUFAs is superior to that of low-dose |
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| Thiazolidinediones (TZD) | ||||||||
| Sepanjnia et al. 2012 | N = 40, 72.5% | 31.4 (5.4) and 32.7 (5.4) | citalopram (30 mg) + pioglitazone (15 mg BID) | citalopram (30 mg) + placebo | DSM-IV MDD | None | HDRS, 6-week RCT | mean difference favouring pioglitazone (−3.4 (−5.6 to −1.2)). |
| Kashani et al. 2013 | N = 50, 100%, | 21.2 (3.3) and 20.3 (4.6) | pioglitazone (15 mg BID) | metformin (750 mg BID) | DSM-IV MDD | PCOS | HDRS, 6-week RCT | percentage reduction favouring pioglitazone [38.3% versus 8.3% reduction from baseline scores, F (1, 37) = 73.513, p < 0.001]. |
| Lin et al. 2015 | N = 37, 78.4% | 49.4 (15.1) and 43.3 (11.8) | pioglitazone (30 mg) +TAU | placebo + treatment as usual | DSM-IV MDD | None | HDRS, 12-week RCT | no significant difference in mean decline of HDRS-21 scores between treatment groups (t [29] = −1.22, p = 0.23). |
| Glucagon-Like Peptide 1 (GLP-1) Agonists | ||||||||
| Mansur et al. 2017 | N = 19, 57.9% | 38.2 | liraglutide (1.8 mg) + TAU | DSM 5 MDD or BD | measurable impairment in executive function | TMTB, 4-week open-label | significant improvement in TMTB standard score with those with higher baseline BMI and IR having the best improvement (Cohen’s d = 0.64, p = 0.009). |
|
| Metformin (MET) | ||||||||
| Guo et al. 2014 | N= 58, 37.9%, | 54.7 (7.3) and 53.3 (7.3) | Metformin (1–2 g per day) | placebo | DSM-IV MDD | Diabetes Mellitus type 2 | wechsler memory scale–revised and MADRS, 24-week RCT | significant improvement in verbal memory index, visual memory index, general memory index, and delayed memory index compared to placebo. metformin significantly decreased MADRS (F 1112 = 26.43; p < 0.001 Metformin significantly decreased MADRS compared to placebo (F = 26.43; p < 0.001) MET metformin significantly decreased MADRS (F 1112 = 26.43; p < 0.00 |
| Abdallah et al. 2020 | N = 80, 47.5% | 34.1 (8.4) and 35.1 (8.0) | metformin (1 g) + fluoxetine (20 mg) | placebo + fluoxetine 20 mg | DSM-IV MDD | none | HDRS, 12-week RCT | 12 week results favouring metformin LSMD −3.454, p = 0.000 |
| Insulin | ||||||||
| Cha et al. 2017 | N = 35, 62.9% | 47.1 (9.9) | intranasal insulin (40 International Units (IU) QID) | placebo | DSM-IV MDD | none | positive and negative affect schedule (PANAS) and global index of neurocognition, 12-week cross over RCT | no between group differences observed |
HDRS: hamilton depression rating scale; RCT: Randomized Controlled Trial; SMD: Standard Mean Difference; TMTB: trail-making test- B; CABG: coronary artery bypass graft surgery; BMI: body mass index; IR: insulin resistance; MADRS: Montgomery–Åsberg Depression Rating Scale; TAU: treatment as usual; RCT: Randomized Controlled Trial. * age is reported for active medication group and then comparator group.